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Sensory Influence on Homeostasis and Lifespan: Molecules and Circuits

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Author Information and Affiliations

Protein Metabolism and Homeostasis in Aging edited by Nektarios Tavernarakis.
©2009 Landes Bioscience and Springer Science+Business Media.
Read this chapter in the Madame Curie Bioscience Database here.

The animal's ability to maintain homeostasis in response to different environments can influence its survival. This chapter will discuss the mechanisms by which environmental cues act through sensory pathways to influence hormone secretion and homeostasis. Interestingly, recent studies also show that there is a sensory influence on lifespan that requires the modulation of hormonal signaling activities. Thus, this raises the possibility that the sensory influence on homeostasis underlies the sensory influence on lifespan.


To optimize survival, animals must maintain relative constancy within their internal environment, also known as homeostasis, by adjusting their physiology in response to their changing external environment. Thus, animals employ many mechanisms to: (1) define set points at which different physiological processes function most efficiently under given conditions; and (2) prevent large deviations from these defined set points.

Internal vs. External Sensors

Specification of these set points, such as blood glucose levels, is subject to internal and external stimuli that are detected by different types of sensors. The sensors that detect internal stimuli typically monitor quantitative differences between set points and the existing internal environment. Since many of these internal sensors are involved in transmitting signals through negative feedback systems that correct deviations back to predetermined set points, these homeostatic sensors are required to function with a high level of precision.1,2 An example of a homeostatic internal sensor is the enzyme glucokinase in the pancreatic β cell, which is a sensor for internal glucose levels to control ATP concentrations and thus insulin secretion from pancreatic β cells.2,3 The mechanisms by which internal sensors regulate animal homeostasis will not be discussed further here and are reviewed elsewhere.2,4-6 Rather, this chapter will focus on the role of external cues and their sensors in influencing homeostasis by modulating defined set points.

The sensors that detect external stimuli generally play a more important role in assessing qualitative differences between various external environments.7,8 Accordingly, external sensors can function with a relatively lower degree of precision to perceive a wider range of concentrations of specific stimuli.7,8 Indeed, such external sensors are less likely involved in rectifying fluctuations from set points but are more likely involved in modulating or resetting the set points.

This chapter will discuss (1) how external sensory inputs are recognized and transduced by their respective sensory cells; and (2) how such sensory information is further processed to modulate the secretion of peptide hormones that maintain homeostasis by regulating different physiological processes. Since external sensory cues and the sensory system have recently been shown to influence lifespan,9-11 this chapter will also address possible mechanisms involved in the sensory influence on aging, which includes progressive impairment of animal homeostasis.

How External Sensory Cues Influence Homeostasis

Although the different roles of external sensory cues in affecting behavior are well-documented, the influence of these cues on animal homeostasis is less appreciated. Since some of these cues have been shown to affect different physiological processes, it is not surprising that there will also be a sensory influence on homeostasis, as demonstrated by a few examples discussed in subsequent sections.

Sensory cues influence homeostasis by modulating hormone secretion. This can be summarized in a simple regulatory motif consisting of three steps (Fig. 1). In step 1, sensory cues change the activity of sensory neurons. In step 2, the sensory information is processed and transmitted, which leads to step 3, where neuro- or nonneuronal endocrine cells secrete hormones required in maintaining homeostasis. All three steps can occur via intracellular signaling within the sensory neuron itself (e.g., release of insulin-like-peptides from C. elegans sensory neurons12). Alternatively, these steps could occur over many cells: the sensory neuron could activate sensory neural circuits that signal target cells to secrete the hormone. The target cells may be other neurons where hormone secretion is activated by neurotransmitters that are released from presynaptic neurons (e.g., hormone secretion from hypothalamic areas downstream of visual sensation13,14); or nonneuronal endocrine organs where the neurotransmitters activate secretion via intercellular signaling cascades (e.g., cephalic-phase insulin secretion from β-cells in response to cholinergic innervations15,16).

The subsequent sections will first describe the molecular components of signaling pathways involved in the reception and transmission of sensory signals and then illustrate examples of sensory and neuroendocrine circuits across which these molecular signaling mechanisms operate.

Molecular Mechanisms Linking Sensory Transduction and Hormonal Outputs

In sensory transduction and hormone secretion, information is converted from one form to another, e.g., from light or chemicals to neuronal activity, or from neurotransmitters to hormone secretion. We summarize the signal transduction pathways involved in these forms of information conversion: from reception of sensory cues, processing and transmission of sensory information, to hormone secretion (Fig. 1).

Receptors That Link External Inputs to Regulated Secretion

The detection of extracellular signals in sensory transduction and hormone secretion commonly relies on two types of receptors: (1) ionotropic receptors that are ion channels that open to allow ion flow when stimulated by an external cue, thereby changing the membrane potential17; and (2) G-protein coupled receptors (GPCRs) that are seven transmembrane proteins that activate heterotrimeric G-proteins subsequent to its own activation18 (Fig. 1). Heterotrimeric G-protein complexes consists of Gα, Gβ and Gγ subunits and are associated with GPCRs in the inactive state, where GDP is bound to the Gα subunit.18,19 Upon GPCR activation, GDP is exchanged with GTP and the G-protein complex dissociates into active Gα and Gβγ subunits that signal to downstream effectors; mechanisms of G-protein activation and its associated proteins are detailed elsewhere.18-21

Figure 1.. A regulatory motif for the sensory influence on homeostasis.

Figure 1.

A regulatory motif for the sensory influence on homeostasis. A) Sensory neurons convert various cues to neural activity. Sensory neuron activity is propagated through neural circuits, where information processing and transmission occurs via inter- and intracellular signals. Ultimately, the neural circuits signal to neuroendocrine cells or endocrine organs, which lead to the release of hormones that alter the physiological state of the animal. Multiple regulatory motifs may be combined into a signaling network, allowing cross-talk between physiological and sensory processes117. B) A schematic diagram showing the molecular nature of sensory transduction pathways that lead to neurotransmitter or hormone release. C) A scheme demonstrating the flow of sensory information that leads to the secretion of hormones that regulate homeostasis. In some cases, the activated sensory neuron releases the hormone itself through an intracellular signaling cascade, like the one depicted in panel B.

Secretory Pathways for Chemical Signals

G-protein signaling and changes in membrane potential regulate the secretion of neurotransmitters that signal across synapses, as well as that of hormones that regulate physiology and homeostasis. Secretion occurs via the fusion of either one of two general types of vesicles with the plasma membrane: synaptic vesicles (SVs) and dense core vesicles (DCVs).22,23 SVs and DCVs differ in their cargo: SVs typically deliver small molecule neurotransmitters, such as γ-aminobutyric acid (GABA), acetylcholine or glutamate, that signal to their cognate receptors across a synapse, whereas DCVs typically release neuropeptides, hormones, such as insulin, and other neurotransmitters.22,23 SVs and DCVs also differ in their biogenesis, trafficking, cell biology and regulation.22,23

The secretion from SVs and DCVs are both tightly controlled; these vesicles progress through a sequence of docking (where vesicles become tightly apposed to the plasma membrane), priming (where vesicles become fusion-competent) and a SNARE-dependent vesicle fusion triggered by intracellular calcium (Ca2+).24-26 The secretory machinery of SVs and DCVs can be regulated at multiple points: the structure and function of release sites (active zones); the activity states of the exocytotic machinery that influence progression through docking, priming and fusion; and the membrane potential that affects Ca2+ entry for triggering vesicle fusion.24-26 G-protein pathways may influence any of these processes, whereas ionotropic receptors primarily affect membrane potential and hence Ca2+ entry.24-26

Regulation of Secretion by Different G-Proteins and Their Effectors

Different Gα subunits regulate different sets of downstream effectors that target different steps in secretion.19q, Gαs and Gαi/o are the major types of Gα subunits involved in this process.27-29 Generally, secretion is promoted by Gαq and Gαs and inhibited by Gαi/o.27-29 Below, we describe some of the more prominent G-protein targets in secretion, not as a comprehensive list but to provide a flavor for the molecules involved.

q activates phospholipase C-β (PLCβ), which cleaves phosphatidylinositol bisphosphate (PIP2) to generate the second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3).29 To stimulate secretion, DAG activates protein kinase C (PKC) and UNC-13 family members,23,29-32 while IP3 activates the IP3 receptor.29 UNC-13 family members have been proposed to affect both priming and additional unknown step(s) in vesicle fusion,31-33 whereas PKC is thought to influence secretion by phosphorylating targets involved in priming and fusion pore formation.34 On the other hand, IP3 receptor activation leads to Ca2+ release from the endoplasmic reticulum and the opening of a cation-selective (Na+/Ca2+ exchanger) channel on the cell membrane.35,36

s activates adenyl cyclase to produce cyclic AMP (cAMP), which activates protein kinase A (PKA) and the exchange protein activated by cAMP (Epac) to stimulate secretion. Downstream targets of PKA and Epac include proteins involved in secretory SNARE complex formation during priming (e.g., tomosyn), proteins in SV-release sites (e.g., RIM1) and ion channel subunits that regulate membrane potential and Ca2+ entry for exocytosis.37,38olf are mammalian olfactory G-proteins related to Gαs and act on similar targets.39,40

i/o inhibits the activity of adenyl cyclase and also targets calcium and potassium channels. These pathways also influence secretion by regulating active zone proteins41,42 and the Rho family of small GTPases that in turn affect actin rearrangements.28 On the other hand, transducin, which is related to the Gαi/o, activates cGMP phosphodiesterase (PDE), which leads to the closing of cGMP-gated cation channels, a block in sodium cation (Na+) influx, hyperpolarization of the cell membrane and neurotransmitter release at synapses.35,36

Regulatory interactions between these distinct G-proteins and their effectors allow cells to integrate inputs from multiple signals. For example, in C. elegans, double mutant analyses have revealed opposing endogenous interactions between Gαq and Gαo.43 These pathways target different synaptic proteins within C. elegans motorneurons, suggesting that their effects on different rate-limiting steps of the secretory process are integrated by the neuron.30,41,42

Specificity in Signaling and Secretion

Specific GPCRs are coupled to specific G-proteins with specific targets, leading to different secretory outcomes. For example, pancreatic β cells express a whole plethora of GPCRs involved in regulating insulin secretion,44 including the M3 muscarinic receptors and the Y1 receptor. Activation of M3 muscarinic receptors by acetylcholine released from parasympathetic nerves that innervate the pancreatic cells, promotes insulin secretion, because M3 muscarinic receptors are coupled to Gαq.44 In contrast, activation of the Y1 GPCRs by its ligand neuropeptide Y leads to inhibition of insulin secretion, because Y1 receptors are coupled to inhibitory G proteins, like Gαi.44 Thus, the outcome of GPCR activation depends on the G-protein to which the GPCR is coupled. A review by Oldham and Hamm20 further discusses the specificity determinants of GPCR/G-protein coupling and the mechanisms of G protein activation.

Similarly, the ion-selectivity of an ionotropic receptor allows it to alter the membrane potential and thus promote or inhibit Ca2+ entry via voltage-gated Ca2+ channels, which subsequently modulate neurotransmitter/hormone secretion.17 For example, at synapses, GABAA receptors on the postsynaptic neuron are inhibitory because they are permeable to chloride anions (Cl-), whereas the AMPA receptor for glutamate are excitatory because they are permeable to cations.17

Examples of Sensory Signal Transduction

Visual cues (light): Light is detected in photoreceptor cells by rhodopsins, which are composed of the G protein-coupled receptor opsin and a chromophore.35,36 Light energy isomerizes the chromophore, which causes receptor conformational changes and activation of a G protein: transducin in vertebrates and a Gαq in invertebrates.35,36 In vertebrates, transducin/PDE activation results in membrane hyperpolarization via inhibition of cGMP-gated channels, whereas in invertebrates Gαq/PLC/IP3 activation leads to depolarization via Ca2+ signals and Na+/Ca++ exchangers.35,36 Despite these differences, these signals lead to changes in neurotransmitter secretion that are propagated through the visual neural circuitry.35,36

Olfactory cues: In many species, odors are detected by a large repertoire of olfactory GPCRs that signal to downstream targets with species specificity.45 In mammals, stimulating olfactory GPCRs lead to the sequential activation of Gαolf, membrane adenyl cyclases and cAMP to activate cyclic nucleotide-gated channels.39 In C. elegans, different olfactory neurons utilize different signaling pathways. Certain olfactory neurons signal via ODR-3 (related to Gαi/o), cGMP and the TAX-2/TAX-4 cGMP-gated ion channel; whereas other olfactory neurons signal via phospholipids, polyunsaturated fatty acids and the OSM-9 TRPV cation channel.46 In contrast, Drosophila utilizes a different family of olfactory seven-pass membrane receptors,47,48 as well as a class of ionotropic glutamate receptor-related proteins,49 which act as ion channels.

Gustatory cues: In mammals, salty and sour tastants are thought to be sensed by ionotropic receptors, whereas sweet, bitter and umami are sensed by GPCRs that couple to gustducin or Gαi.50 In Drosophila, the gustatory receptors (GRs) are related to Drosophila olfactory receptors.51,52 GR5a and Gr64a act in sugar sensing, but neither the downstream signal tranduction pathways nor the receptors for other tastants are fully known.51,52 In C. elegans, gustatory receptors have not been identified, but Na+ and Cl- ions are sensed separately by bilaterally asymmetric ASE sensory neurons via a guanyl cyclase signaling pathway46 that is modulated by G-protein signaling in other sensory neurons.53

The Circuitry Underlying the Processing of Sensory Information

The architecture and function of the nervous system of one animal species can vary significantly to those of others and their description lies beyond the scope of this chapter. Rather, this section will focus on examples of neural circuitry involved in sensory processing to illustrate how visual and chemosensory cues can elicit systemic changes by regulating hormonal secretions from target tissues (Fig. 1), which affect animal homeostasis.

Processing of Visual Information to Synchronize Circadian Rhythms

Circadian behavioral and physiological rhythms have evolved in eukaryotes as a means to anticipate environmental changes that occur regularly with the earth's rotation around its axis. In mammals, the time-keeping mechanism that generates these rhythms involves circadian clocks that function within a hierarchy.8 A master clock resides in neurons of the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes the clocks of all peripheral cells within the animal.54-56 The master clock in the SCN is capable of self-sustained function,54 whereas the peripheral clocks oscillate only in the presence of the master clock.55,56 On the molecular level, each clock consists of an oscillatory gene-regulatory network that has been reviewed extensively by others57 and will not be addressed here further.

A major stimulus in resetting the circadian clock is the cycle between the presence and absence of light within the animal's daily environment.8 This visual cue is communicated directly to the master clock in the SCN from a subset of photoreceptor cells that express melanopsin, a rhodopsin-related molecule.58,59 The axons of the melanopsin-expressing cells relay photic information by releasing the neurotransmitter glutamate that acts on the SCN to promote molecular changes that resynchronize the clock with the animal's light/dark environmental cycle.60 The SCN secretes signals, like the peptide hormones prokineticin 213 and transforming growth factor α (TGF-α),14 that can then act on other areas of the hypothalamus.61 These other hypothalamic areas in turn control the secretion of hormones from target endocrine tissues, such as the pituitary, pineal and adrenal glands, which allows for the circadian modulation of many physiological processes required for homeostasis.61

Glucose homeostasis is one example that undergoes circadian rhythmicity: blood glucose levels are higher during the light phase of the cycle and lower during the dark phase of the cycle.62,63 Although these diurnal changes in blood glucose levels could be explained simply by a circadian schedule in the animal's food intake, the perception of light has been shown to affect the levels of melatonin,64,65 which can stimulate insulin pathway activity and glucose transport into cells.62,63 The synthesis of the hormone melatonin in the pineal gland is inhibited by the presence of light:64 there is less circulating melatonin during the light phase of the cycle and more melatonin during the dark phase of the cycle. In addition, this diurnal cycling in melatonin synthesis can be abolished by the removal of retinal photoreceptors or by the disruption of the circuit between the photoreceptor cells and the pineal gland.65 Thus, these observations together suggest a role for light perception in glucose homeostasis.

Processing of Chemosensory Information to Alter Behavior and Metabolism

Gustatory and olfactory cues are not only perceived by anatomically distinct receptor cells but are also processed by separate circuits in different species.

Worms: In C. elegans, a subset of gustatory neurons66,67 senses a pheromone mixture of glycosides68,69 that promotes under harsh environments dauer formation, which is an alternative developmental program.70-72 Harsh conditions, like overcrowding and hence low food availability, can be signified by increasing environmental quantities of the dauer pheromone mixture, which is secreted by each animal throughout its life.70,71 Accordingly, high concentrations of dauer pheromone have been shown to inhibit the secretion of peptide hormones, such as an insulin-like peptide12 and TGF-β,67 from the pheromone-sensing neurons, which in turn can act directly on neuronal (e.g., interneurons) and/or nonneuronal cells. The downregulation of the insulin70,73 or the TGF-β67,70 pathway promotes formation of the developmentally arrested dauers. Hence, inhibiting the release of these hormones from the chemosensory neurons is believed to promote a shift not only in the animal's metabolic homeostasis but also in its stress-responsiveness that prepares the dauer for long-term survival under harsh conditions.74,75 At present, the cells on which these peptides act to regulate dauer formation are unknown.

On the other hand, the role of C. elegans olfactory neurons in regulating homeostasis remains unclear, although these neurons have been shown to affect lifespan10 (discussed below), which could involve a change in the animal's homeostasis. The neuronal circuitries that process olfactory cues in contrast to gustatory cues are also only beginning to be elucidated. For example, the map of postsynaptic partners of gustatory and olfactory neurons shows considerable overlap.76 However, olfactory neurons synapse more extensively onto one set of interneurons, whereas gustatory neurons synapse more onto another set of neurons.76

Fruitflies: In Drosophila, the neurons that detect gustatory and olfactory stimuli are found in anatomically different structures.77 Taste inputs are communicated either directly or indirectly to the subesophageal ganglion (SOG), which further relays taste information not only to higher brain centers, the ventral nerve cord and nonneuronal tissues but also to neuroendocrine cells.77,78 This raises the possibility that gustatory cues can also modulate the release of hormones that regulate fly homeostasis. Interestingly, a small cluster of SOG neurons that express the neuropeptide hugin, which controls food intake and fly growth, not only receive direct inputs78 from gustatory receptor neurons (that innervate structures within the fly's mouthparts)79 but also send projections to or near insulin-producing cells.78 In addition, consistent with the hypothesis that SOG peptides are regulated by gustatory cues that affect homeostasis, microarray analysis of hugin mutants demonstrates altered expression of insulin-like peptides.78

Recently, fly olfactory mutants have also been shown to have altered lipid content and respiration,11 which suggests a role for olfactory cues in maintaining this animal's metabolic homeostasis. The cholinergic olfactory receptor neurons convey odor inputs directly to individual glomeruli in the fly antennal lobe, where olfactory information is further relayed to second-order cholinergic projection neurons (PNs).77 PNs link the antennal lobe with higher brain centers, like the mushroom body, which is involved not only in associative olfactory learning77 but also in other processes, including sleep homeostasis.80,81

Mammals: The homeostatic mechanisms that are activated upon food intake are influenced, not surprisingly, by chemosensory cues.82 Food intake elicits a wide range of responses that serve to ensure effective digestion, maintenance of metabolic homeostasis upon the availability of new nutrients and termination of feeding upon the release of a satiety signal.83 The physiological responses during mammalian food intake can be divided into three phases, depending on the tissues that are stimulated during the process: the neural/cephalic phase, the gastric phase and the intestinal phase.82 The cephalic phase of food intake is studied by subjecting the animal to food odors alone or to mock feedings that involve tasting but not swallowing or digesting the food. This initial phase of food intake implicates odorants and tastants in triggering secretions from the salivary glands, stomach and pancreas.36,82 For example, there is an increased secretion of saliva,84 the gastrin hormone and gastric acid85 upon smelling or tasting palatable food. Moreover, after a mock feeding, there is increased secretion of the hormones leptin86 and insulin, which occurs in the absence of increased blood glucose levels,15,16 in rodents, dogs or humans. These pre-absorptive, anticipatory responses that are triggered by gustatory and olfactory stimuli have been shown to be required for normal feeding behavior and optimal digestion82 and suggest how taste and olfaction influence an animal's metabolic homeostasis.

Gustatory information from taste receptors on the tongue is carried through three different cranial nerves—the facial, the glossopharyngeal and the vagus nerves—to the nucleus of the solitary tract (NST) in the mammalian brain.36,87 From the NST, which also receives internal viscerosensory inputs, gustatory information is relayed to the parabrachial nucleus (PbN), which further projects to the thalamus and gustatory cortex.36,87 In primates, the thalamocortical part of the circuit that comes from the NST bypasses the PbN neurons.36,87 Interestingly, gustatory information can also be relayed in a parallel circuit not only to the amygdala but also to the hypothalamus,36,87 which links the mammalian nervous system to the endocrine system.

On the other hand, olfactory information is transmitted by olfactory receptor neurons (ORNs) to the first relay point within the brain, the olfactory bulb.36,88 From there, olfactory information is relayed to cortical regions, as well as amygdalar and hypothalamic regions.36 Indeed, retrograde labeling of neurons has demonstrated that a discrete set of ORNs relays information to hypothalamic neurons that express the luteinizing hormone release hormone (LHRH), which is a key hormone that regulates mammalian reproductive homeostasis.89 Consistent with the existence of this neural circuitry, olfactory cues have also been shown to stimulate the secretion of LHRH, which not only controls the release of other hormones required for gonadal development and function but may also directly promote mating behavior.90,91

Thus, together these gustatory and olfactory circuits can allow the hypothalamus to integrate both external and internal sensory information to control animal homeostasis in response to the changing quality of the environment.

Sensory Influence on Lifespan

Recent studies have shown that the sensory systems of C. elegans and Drosophila not only influence the behavior and physiology of these animals but also their lifespan.9-11 A subset of gustatory and olfactory neurons in C. elegans10 and olfaction in Drosophila11 have been found to exert different effects on lifespan, which suggests that food-derived cues affect longevity. Since dietary restriction has previously been shown to increase lifespan,92 it is possible that the sensory system influences lifespan by regulating the animal's general food intake. However, the observation that not every gustatory neuron affects lifespan10 suggests that the animal adjusts its rate of aging not only in response to food levels but also to more specific cues derived from different food sources.

Gustatory Influence on the Insulin/IGF-1 Pathway That Affects Lifespan

Laser ablation of certain gustatory neurons (ASI and ASG) extends C. elegans lifespan, which depends on the activities of other gustatory neurons (ASJ and ASK).10 This suggests that there are two classes of gustatory neurons: one that shortens lifespan and another that lengthens lifespan. These neurons appear to influence lifespan by modulating the activity of the C. elegans insulin/IGF-1 pathway,10 which has been shown previously to modulate longevity73,93-96 (Fig. 2).

The reduction in function of the C. elegans insulin/IGF-1 receptor DAF-2 can increase lifespan by as much as two-fold.73,93,94 This lifespan extension requires the activity of DAF-16,93,94 a FOXO transcription factor95,96 that is activated and translocated into the nucleus upon low DAF-2 activity.97-99 Mutations that impair C. elegans sensory function decrease the activity of the DAF-2 pathway,9 leading to the nuclear localization of DAF-16.98 In addition, ablation of the ASI neurons causes lifespan extension that is daf-16-dependent, whereas ablation of the ASJ and ASK neurons can partly suppress the lifespan extension observed in daf-2 reduction-of-function mutants (Fig. 2).10 Thus, these findings, together with the expression of insulin-like peptides in sensory neurons,12,100 are in keeping with the idea that the activity of this pathway is subject to modulation by sensory cues.

Olfactory Influence on Signal(s) from the Reproductive System That Affect Lifespan

Ablation of the germline precursor cells extends C. elegans lifespan, which can be suppressed by either ablation of the somatic gonad precursor cells or a null mutation in daf-16.101 In contrast, daf-16 null mutants in which the somatic gonad has been ablated live shorter than daf-16 mutants with an intact gonad,101 suggesting that the somatic gonad can act in parallel to daf-16 to affect lifespan. These observations have led to the model that the germ line of C. elegans generates a longevity-inhibiting, daf-16-dependent signal, which is counterbalanced by a longevity-promoting, daf-16-independent signal from the somatic gonad (Fig. 2).101

Germline ablation can further extend the lifespan of C. elegans that have sensory defects,9 which can either be gustatory or olfactory in nature.10 Surprisingly, however, impairment of olfactory, but not gustatory, function prevents somatic gonad ablation from suppressing the lifespan extension caused by germline ablation.10 This suggests that, in contrast to gustatory neurons, olfactory neurons modulate the activity of the somatic gonad signal (Fig. 2).10 Consistent with this observation, the olfactory influence on lifespan is also at least partly daf-16-independent.10 However, the somatic gonad appears to promote longevity in a daf-2-dependent manner,101 which raises the possibility that olfactory neurons might influence lifespan by also regulating the release of insulin-like peptides that, in this case, act independently of daf-16. Indeed, at least one of the worm insulin-like genes is expressed in a pair of olfactory neurons.102 So far, it is unclear whether olfactory neurons release a signal that modulates DAF-2 activity or whether DAF-2 blocks the release of a signal from the olfactory neurons to inhibit longevity.

Figure 2.. Specific gustatory and olfactory neurons influence C.

Figure 2.

Specific gustatory and olfactory neurons influence C. elegans lifespan through hormonal signaling pathways. A) Certain gustatory neurons (ASI, ASG) shorten lifespan, whereas other neurons (ASJ, ASK) lengthen lifespan. Both classes of gustatory neurons appear to modulate insulin/IGF-1 signaling to affect worm lifespan. B) A schematic diagram of the worm's gonad precursor cells showing that the germline cells (GC, gray circles) inhibit longevity in a daf-16-dependent manner. On the other hand, the somatic gonad (SG, white circles) promotes longevity in an olfactory neuron-dependent and daf-2-dependent manner.

The olfactory influence on lifespan has also been reported in Drosophila.11 Flies that lack the atypical olfactory receptor Or83b, which is required for the proper subcellular localization of many of the olfactory receptors,103 not only have severe olfactory deficits but also live long.11 Conversely, olfaction has been shown to shorten the lifespan of dietary-restricted flies.11

Dietary restriction (DR) is a treatment that can extend the lifespan of many species, ranging from yeast to mammals.92,104-106 DR, by its very nature, indicates a role for the environment in influencing lifespan. Since the lifespan increase seen in dietary-restricted flies can be partly suppressed when the flies are exposed to food-associated odors alone,11 it appears that sensory perception itself can trigger a physiological change that can antagonize the DR response. In long-lived Or83b mutant flies, the mRNA levels of most of the insulin-like genes are not significantly downregulated, with the exception of one member of this family.11,107 Since the insulin pathway has also been shown to affect fly lifespan,108-112 it is possible that the change in expression of one of the insulin-like genes mediates the olfaction-induced physiological change that affects lifespan. Although the mechanism behind this sensory influence on lifespan currently remains unknown, it is not surprising that the olfactory system, which can signal the levels or quality of food in the environment, would mediate, at least in part, the effects of DR on lifespan extension.

Conclusion: Connections Between the Sensory Influence on Homeostasis and Lifespan?

The sensory influence on both homeostasis and lifespan involves the modulation of activities of hormonal signaling pathways. One of these pathways, the insulin/IGF-1 pathway, has been shown to regulate the expression of metabolic, immune-response and stress-response genes that not only regulate animal homeostasis but also affect lifespan.113,114 Together these observations are consistent with the possibility that specific sensory cues can redefine set points in homeostasis bidirectionally, thus leading to a longer or shorter lifespan. This hypothesis predicts that the effects of a given sensory cue on lifespan will be abolished when either the specific sensory pathway or its modulation of the set point(s) is disrupted. Indeed, sensory neurons have been shown to control lipid homeostasis115 and a change in lipid homeostasis can also lead to changes in lifespan.116 Thus, the future identification of the set points affected by the lifespan-influencing sensory cues should yield insight into the mechanisms that regulate the rate and/or onset of aging.

Finally, homeostasis is characterized by a number of feedback mechanisms. Since hormones have also been proposed to modulate the sensory system,117 this raises another intriguing possibility that the decline in sensory function observed during aging118 may result from a disruption in feedback regulation between the animal's sensory system and its different homeostatic mechanisms.


We apologize to the authors whose work we were unable to cite due to space constraints. We would also like to thank P. Caroni, R. Friedrich, A. Matus, F. Meins, M. Noll and M. Raff for comments on a previous version of this manuscript. This work was supported by the Novartis Research Foundation (J. A. and W. M.), a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship (MA-3995/1; W. M.) and an RCUK Fellowship (Q.C.).


Nelson DL, Cox MM, editors. Principles of Biochemistry. 5th ed. New York: W.H. Freeman and Company; 2008. Lehninger.
Newsholme P, Bender K, Kiely A, et al. Amino acid metabolism, insulin secretion and diabetes. Biochem Soc Trans. 2007;035:1180–1186. [PubMed: 17956307]
German MS. Glucose sensing in pancreatic islet beta cells: The key role of glucokinase and the glycolytic intermediates. Proc Natl Acad Sci USA. 1993;90:1781–1785. [PMC free article: PMC45963] [PubMed: 8446591]
Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165. [PubMed: 16517403]
Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854–859. [PubMed: 17167473]
Nolan CJ, Prentki M. The islet β-cell: fuel responsive and vulnerable. Trends Endocrinol Metab. 2008;19:285–291. [PubMed: 18774732]
Bargmann CI, Hartwieg E, Horvitz HR. Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell. 1993;74:515–527. [PubMed: 8348618]
Challet E, Caldelas I, Graff C, et al. Synchronization of the molecular clockwork by light- and food-related cues in mammals. Biol Chem. 2003;384:711–719. [PubMed: 12817467]
Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature. 1999;402:804–809. [PubMed: 10617200]
Alcedo J, Kenyon C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron. 2004;41:45–55. [PubMed: 14715134]
Libert S, Zwiener J, Chu X, et al. Regulation of Drosophila life span by olfaction and food-derived odors. Science. 2007;315:1133–1137. [PubMed: 17272684]
Li W, Kennedy SG, Ruvkun G. daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev. 2003;17:844–858. [PMC free article: PMC196030] [PubMed: 12654727]
Prosser HM, Bradley A, Chesham JE, et al. Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc Natl Acad Sci USA. 2007;104:648–653. [PMC free article: PMC1761911] [PubMed: 17202262]
Kramer A, Yang F-C, Kraves S, et al. A screen for secreted factors of the suprachiasmatic nucleus. Methods Enzymol. 2005;393:645–663. [PubMed: 15817317]
Berthoud HR, Trimble ER, Siegel EG, et al. Cephalic-phase insulin secretion in normal and pancreatic islet-transplanted rats. Am J Physiol. 1980;238:E336–E340. [PubMed: 6769337]
Secchi A, Caldara R, Caumo A, et al. Cephalic-phase insulin and glucagon release in normal subjects and in patients receiving pancreas transplantation. Metabolism. 1995;44:1153–1158. [PubMed: 7666788]
Barrera NP, Edwardson JM. The subunit arrangement and assembly of ionotropic receptors. Trends Neurosci. 2008;31:569–576. [PubMed: 18774187]
Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3:639–650. [PubMed: 12209124]
Simon MI, Strathmann MP, Gautam N. Diversity of G proteins in signal transduction. Science. 1991;252:802–808. [PubMed: 1902986]
Oldham WM, Hamm HE. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol. 2008;9:60–71. [PubMed: 18043707]
Pierce KL, Lefkowitz RJ. Classical and new roles of β-arrestins in the regulation of G-PROTEIN-COUPLED receptors. Nat Rev Neurosci. 2001;2:727–533. [PubMed: 11584310]
Edwards RH. Neurotransmitter release: variations on a theme. Curr Biol. 1998;8:R883–885. [PubMed: 9843673]
Xu T, Xu P. Searching for molecular players differentially involved in neurotransmitter and neuropeptide release. Neurochem Res. 2008;33:1915–1919. [PubMed: 18401709]
Südhof TC. The synaptic vesicle cycle. Annu Rev Neurosci. 2004;27:509–547. [PubMed: 15217342]
Südhof TC, Rothman JE. Membrane fusion: grappling with SNARE and SM proteins. Science. 2009;323:474–477. [PMC free article: PMC3736821] [PubMed: 19164740]
Wojcik SM, Brose N. Regulation of membrane fusion in synaptic excitation-secretion coupling: speed and accuracy matter. Neuron. 2007;55:11–24. [PubMed: 17610814]
Neves SR, Ram PT, Iyengar R. G protein pathways. Science. 2002;296:1636–1639. [PubMed: 12040175]
Jiang M, Bajpayee NS. Molecular mechanisms of Go signaling. Neurosignals. 2009;17:23–41. [PMC free article: PMC2836949] [PubMed: 19212138]
Mizuno N, Itoh H. Functions and regulatory mechanisms of Gq-signaling pathways. Neurosignals. 2009;17:42–54. [PubMed: 19212139]
Sieburth D, Madison JM, Kaplan JM. PKC-1 regulates secretion of neuropeptides. Nat Neurosci. 2007;10:49–57. [PubMed: 17128266]
Betz A, Ashery U, Rickmann M, et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998;21:123–136. [PubMed: 9697857]
Rhee JS, Betz A, Pyott S, et al. β phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002;108:121–133. [PubMed: 11792326]
Madison JM, Nurrish S, Kaplan JM. UNC-13 interaction with syntaxin is required for synaptic transmission. Curr Biol. 2005;15:2236–2242. [PubMed: 16271476]
Morgan A, Burgoyne RD, Barclay JW, et al. Regulation of exocytosis by protein kinase C. Biochem Soc Trans. 2005;33:1341–1344. [PubMed: 16246114]
Yarfitz S, Hurley JB. Transduction mechanisms of vertebrate and invertebrate photoreceptors. J Biol Chem. 1994;269:14329–14332. [PubMed: 8182033]
Squire LR, Bloom FE, Roberts JL, et al., editors. USA: Elsevier Science; 2003. Fundamental Neuroscience 2nd ed.
Baba T, Sakisaka T, Mochida S, et al. PKA-catalyzed phosphorylation of tomosyn and its implication in Ca2+-dependent exocytosis of neurotransmitter. J Cell Biol. 2005;170:1113–1125. [PMC free article: PMC2171531] [PubMed: 16186257]
Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005;85:1303–1342. [PubMed: 16183914]
Ronnett GV, Moon C. G proteins and olfactory signal transduction. Annu Rev Physiol. 2002;64:189–222. [PubMed: 11826268]
Hasin-Brumshtein Y, Lancet D, Olender T. Human olfaction: from genomic variation to phenotypic diversity. Trends Genet. 2009;25:178–184. [PubMed: 19303166]
Nurrish S, Segalat L, Kaplan JM. Serotonin inhibition of synaptic transmission: Gαo decreases the abundance of UNC-13 at release sites. Neuron. 1999;24:231–242. [PubMed: 10677040]
Ch'ng Q, Sieburth D, Kaplan JM. Profiling synaptic proteins identifies regulators of insulin secretion and lifespan. PLoS Genet. 2008;4 e1000283. [PMC free article: PMC2582949] [PubMed: 19043554]
Hajdu-Cronin YM, Chen WJ, Patikoglou G, et al. Antagonism between Goα and Gqα in Caenorhabditis elegans: the RGS protein EAT-16 is necessary for Go signaling and regulates Gqα activity. Genes Dev. 1999;13:1780–1793. [PMC free article: PMC316886] [PubMed: 10421631]
Winzell MS, Ahren B. G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. Pharmacol Ther. 2007;116:437–448. [PubMed: 17900700]
Bargmann CI. Comparative chemosensation from receptors to ecology. Nature. 2006;444:295–301. [PubMed: 17108953]
Bargmann CI, editor. In: T.C.e.R. Community. WormBook; 2006. Chemosensation in C. elegans. http://www.wormbook.org. [PMC free article: PMC4781564] [PubMed: 18050433]
Sato K, Pellegrino M, Nakagawa T, et al. Insect olfactory receptors are heteromeric ligand-gated ion channels. Nature. 2008;452:1002–1006. [PubMed: 18408712]
Wicher D, Schafer R, Bauernfeind R, et al. Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature. 2008;452:1007–1011. [PubMed: 18408711]
Benton R, Vannice KS, Gomez-Diaz C, et al. Variant ionotropic glutamate receptors as chemosensory receptors in Drosophila. Cell. 2009;136:149–162. [PMC free article: PMC2709536] [PubMed: 19135896]
Chandrashekar J, Hoon MA, Ryba NJ, et al. The receptors and cells for mammalian taste. Nature. 2006;444:288–294. [PubMed: 17108952]
Scott K. Taste recognition: food for thought. Neuron. 2005;48:455–464. [PubMed: 16269362]
Benton R. Chemical sensing in Drosophila. Curr Opin Neurobiol. 2008;18:357–363. [PubMed: 18801431]
Hukema R, Rademakers S, Dekkers M, et al. Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis elegans. EMBO J. 2006;25:312–322. [PMC free article: PMC1383522] [PubMed: 16407969]
Welsh DK, Logothetis DE, Meister M, et al. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron. 1995;14:697–706. [PubMed: 7718233]
Sakamoto K, Nagase T, Fukui H, et al. Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J Biol Chem. 1998;273:27039–27042. [PubMed: 9765215]
Yamazaki S, Numano R, Abe M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science. 2000;288:682–685. [PubMed: 10784453]
Dunlap JC. Molecular bases for circadian clocks. Cell. 1999;96:271–290. [PubMed: 9988221]
Hattar S, Liao HW, Takao M, et al. Melanopsin-containing retinal ganglion cells: architecture, projections and intrinsic photosensitivity. Science. 2002;295:1065–1070. [PMC free article: PMC2885915] [PubMed: 11834834]
Provencio I, Rollag MD, Castrucci AM. Anatomy: photoreceptive net in the mammalian retina. Nature. 2002;415:493–493. [PubMed: 11823848]
Ding JM, Chen D, Weber ET, et al. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science. 1994;266:1713–1717. [PubMed: 7527589]
Watts A. The efferent projections of the suprachiasmatic nucleus: anatomical insights into the control of circadian rhythms. New York: Oxford; In: Klein D, Moore R, Reppert S.M, eds. The Suprachiasmatic Nucleus—The Mind's Clock. 1991:77–106.
Ha E, Yim S-V, Chung J-H, et al. Melatonin stimulates glucose transport via insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway in C2C12 murine skeletal muscle cells. J Pineal Res. 2006;41:67–72. [PubMed: 16842543]
la Fleur SE, Kalsbeek A, Wortel J, et al. Role for the pineal and melatonin in glucose homeostasis: pinealectomy increases night-time glucose concentrations. J Neuroendocrinol. 2001;13:1025–1032. [PubMed: 11722698]
Wurtman RJ, Axelrod J, Phillips LS. Melatonin synthesis in the pineal gland: control by light. Science. 1963;142:1071–1073. [PubMed: 14068225]
Wurtman RJ, Axelrod J, Fischer JE. Melatonin synthesis in the pineal gland: effect of light mediated by the sympathetic nervous system. Science. 1964;143:1328–1329. [PubMed: 17799239]
Bargmann CI, Horvitz HR. Control of larval development by chemosensory neurons in Caenorhabditis elegans. Science. 1991;251:1243–1246. [PubMed: 2006412]
Schackwitz WS, Inoue T, Thomas JH. Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron. 1996;17:719–728. [PubMed: 8893028]
Butcher RA, Fujita M, Schroeder FC, et al. Small-molecule pheromones that control dauer development in Caenorhabditis elegans. Nat Chem Biol. 2007;3:420–422. [PubMed: 17558398]
Jeong PY, Jung M, Yim YH, et al. Chemical structure and biological activity of the Caenorhabditis elegans dauer-inducing pheromone. Nature. 2005;433:541–545. [PubMed: 15690045]
Riddle DL, Swanson MM, Albert PS. Interacting genes in nematode dauer larva formation. Nature. 1981;290:668–671. [PubMed: 7219552]
Golden JW, Riddle DL. The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food and temperature. Dev Biol. 1984;102:368–378. [PubMed: 6706004]
Vowels JJ, Thomas JH. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics. 1992;130:105–123. [PMC free article: PMC1204785] [PubMed: 1732156]
Kimura KD, Tissenbaum HA, Liu Y, et al. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997;277:942–946. [PubMed: 9252323]
Wang J, Kim SK. Global analysis of dauer gene expression in Caenorhabditis elegans. Development. 2003;130:1621–1634. [PubMed: 12620986]
Narbonne P, Roy R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature. 2009;457:210–214. [PubMed: 19052547]
White JG, Southgate E, Thomson JN, et al. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci. 1986 [PubMed: 22462104]
Vosshall LB, Stocker RF. Molecular architecture of smell and taste in Drosophila. Annu Rev Neurosci. 2007;30:505–533. [PubMed: 17506643]
Melcher C, Pankratz MJ. Candidate gustatory interneurons modulating feeding behavior in the Drosophila brain. PLoS Biol. 2005;3 [PMC free article: PMC1193519] [PubMed: 16122349]
Scott K, Brady JR, Cravchik A, et al. A chemosensory gene family encoding candidate gustatory and olfactory receptors in Drosophila. Cell. 2001;104:661–673. [PubMed: 11257221]
Joiner WJ, Crocker A, White BH, et al. Sleep in Drosophila is regulated by adult mushroom bodies. Nature. 2006;441:757–760. [PubMed: 16760980]
Pitman JL, McGill JJ, Keegan KP, et al. A dynamic role for the mushroom bodies in promoting sleep in Drosophila. Nature. 2006;441:753–756. [PubMed: 16760979]
Zafra MA, Molina F, Puerto A. The neural/cephalic phase reflexes in the physiology of nutrition. Neurosci Biobehav Rev. 2006;30:1032–1044. [PubMed: 16678262]
Saper CB, Chou TC, Elmquist JK. The need to feed: homeostatic and hedonic control of eating. Neuron. 2002;36:199–211. [PubMed: 12383777]
Richardson CT, Feldman M. Salivary response to food in humans and its effect on gastric acid secretion. Am J Physiol. 1986;250:G85–G91. [PubMed: 2867685]
Feldman M, Richardson CT. Role of thought, sight, smell and taste of food in the cephalic phase of gastric acid secretion in humans. Gastroenterology. 1986;90:428–433. [PubMed: 3940915]
Konturek SJ, Konturek JW. Cephalic phase of pancreatic secretion. Appetite. 2000;34:197–205. [PubMed: 10744910]
Lundy Jr RF, Norgren R. Gustatory system. USA: Elsevier; In: Paxinos G, ed. The Rat Nervous System. 2004:891–921.
Reed R. After the holy grail: establishing a molecular basis for mammalian olfaction. Cell. 2004;116:329–336. [PubMed: 14744441]
Yoon H, Enquist LW, Dulac C. Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell. 2005;123:669–682. [PubMed: 16290037]
Merchenthaler I, Sétáló G, Petrusz P, et al. Identification of hypophysiotropic luteinizing hormone-releasing hormone (LHRH) neurons by combined retrograde labeling and immunocytochemistry. Exp Clin Endocrinol. 1989;94:133–140. [PubMed: 2689189]
Witkin JW, Paden CM, Silverman AJ. The luteinizing hormone-releasing hormone (LHRH) systems in the rat brain. Neuroendocrinology. 1982;35:429–438. [PubMed: 6759973]
Klass MR. Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech Ageing Dev. 1977;6:413–429. [PubMed: 926867]
Kenyon C, Chang J, Gensch E, et al. A C. elegans mutant that lives twice as long as wild type. Nature. 1993;366:461–464. [PubMed: 8247153]
Larsen P, Albert PS, Riddle DL. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics. 1995;139:1567–1583. [PMC free article: PMC1206485] [PubMed: 7789761]
Lin K, Dorman JB, Rodan A, et al. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997;278:1319–1322. [PubMed: 9360933]
Ogg S, Paradis S, Gottlieb S, et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997;389:994–999. [PubMed: 9353126]
Henderson ST, Johnson TE. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001;11:1975–1980. [PubMed: 11747825]
Lin K, Hsin H, Libina N, et al. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet. 2001;28:139–145. [PubMed: 11381260]
Lee RYN, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol. 2001;11:1950–1957. [PubMed: 11747821]
Pierce SB, Costa M, Wisotzkey R, et al. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 2001;15:672–686. [PMC free article: PMC312654] [PubMed: 11274053]
Hsin H, Kenyon C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature. 1999;399:362–366. [PubMed: 10360574]
Kodama E, Kuhara A, Mohri-Shiomi A, et al. Insulin-like signaling and the neural circuit for integrative behavior in C. elegans. Genes Dev. 2006;20:2955–2960. [PMC free article: PMC1620028] [PubMed: 17079685]
Larsson MC, Domingos AI, Jones WD, et al. Or83b encodes a broadly expressed odorant receptor essential for Drosophila olfaction. Neuron. 2004;43:703–714. [PubMed: 15339651]
Lin SJ, Defossez PA, Guarente LS. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000;289:2126–2128. [PubMed: 11000115]
Clancy DJ, Gems D, Hafen E, et al. Dietary restriction in long-lived dwarf flies. Science. 2002;296 [PubMed: 11951037]
McCay CM, Cromwell MF, Maynard LA. The effect of retarded growth upon the length of life span and ultimate body size. J Nutr. 1935;10:63–79.
Brogiolo W, Stocker H, Ikeya T, et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol. 2001;11:213–221. [PubMed: 11250149]
Tatar M, Kopelman A, Epstein D, et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science. 2001;292:107–110. [PubMed: 11292875]
Clancy DJ, Gems D, Harshman LG, et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science. 2001;292:104–106. [PubMed: 11292874]
Broughton SJ, Piper MD, Ikeya T, et al. Longer lifespan, altered metabolism and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci USA. 2005;102:3105–3110. [PMC free article: PMC549445] [PubMed: 15708981]
Giannakou ME, Goss M, Jünger MA, et al. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science. 2004;305 [PubMed: 15192154]
Hwangbo DS, Gersham B, Tu M-P, et al. Drosophila dFOXO controls lifespan and regulates insulin signaling in brain and fat body. Nature. 2004;429:562–566. [PubMed: 15175753]
Lee SS, Kennedy S, Tolonen AC, et al. DAF-16 target genes that control C. elegans life-span and metabolism. Science. 2003;300:644–647. [PubMed: 12690206]
Murphy CT, McCarroll SA, Bargmann CI, et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003;424:277–283. [PubMed: 12845331]
Mak HY, Nelson LS, Basson M, et al. Polygenic control of Caenorhabditis elegans fat storage. Nat Genet. 2006;38:363–368. [PubMed: 16462744]
Wang MC, O'Rourke EJ, Ruvkun G. Fat metabolism links germline stem cells and longevity in C. elegans. Science. 2008;322:957–960. [PMC free article: PMC2760269] [PubMed: 18988854]
Martin B, Maudsley S, White CM, et al. Hormones in the naso-oropharynx: endocrine modulation of taste and smell. Trends Endocrinol Metab. 2009;20:163–170. [PMC free article: PMC2732121] [PubMed: 19359194]
Chauhan J, Hawrysh ZJ, Gee M, et al. Age-related olfactory and taste changes and interrelationships between taste and nutrition. J Am Diet Assoc. 1987;87:1543–1550. [PubMed: 3312375]
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